Edible oils to enhance delivery of orally administered steroids

ABSTRACT

The present invention relates to the formulation of steroids, including neurosteroids (e.g., allopregnanolone (ALP)) in edible oils to enhance their absorption when administered, e.g., orally or transmucosally to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. application Ser. No.14/345,385, filed on Mar. 17, 2014, which is the U.S. National Phaseunder 35 U.S.C. § 371 of Intl. Appl. No. PCT/US2012/056509, filed onSep. 21, 2012, which claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 61/538,546, filed on Sep. 23, 2011, whichare hereby incorporated herein by reference in their entireties for allpurposes.

FIELD OF THE INVENTION

The present invention relates to the formulation of steroids, includingneurosteroids (e.g., allopregnanolone (ALP)) in edible oils to enhancetheir absorption when administered, e.g., orally or transmucosally to apatient.

BACKGROUND OF THE INVENTION

Steroids, including neurosteroids (e.g., allopregnanolone) are highlyinsoluble in aqueous solution. Various approaches are used to enhanceaqueous dissolution, including the use of cyclodextrin solutions.However, even with cyclodextrin as a solvation aid, solubility is notsufficient to permit oral delivery for the treatment of medicalconditions. Another approach that has been used is nanosizing andcoating of nanoparticles, which are then formulated as aqueoussuspensions or pills. Nanosizing and coating has been found to enhanceabsorption and reduce the “food effect” whereby absorption is highlyvariable and dependent upon dosing with or without a fatty meal. Still,this approach requires large amounts of the steroid to be deliveredbecause of poor bioavailability. There is presently no acceptableapproach for the oral delivery of neurosteroids.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compositions comprising a steroidand an edible oil.

In another aspect, the invention provides compositions consistingessentially of a steroid and an edible oil.

In some embodiments, the steroid is a neurosteroid. In some embodiments,the neurosteroid is selected from the group consisting ofallopregnanolone, allotetrahydrodeoxycorticosterone, ganaxolone,alphaxolone, alphadolone, hydroxydione, minaxolone, and Althesin. Insome embodiments, the neurosteroid is allopregnanolone. In someembodiments, the steroid is not progesterone.

In some embodiments, the steroid is suspended or dissolved in the edibleoil. In some embodiments, the edible oil comprises one or more avegetable oils. In some embodiments, the vegetable oil is selected fromthe group consisting of coconut oil, corn oil, cottonseed oil, oliveoil, palm oil, peanut oil, rapeseed oil, canola oil, safflower oil,sesame oil, soybean oil, sunflower oil, and mixtures thereof. In someembodiments, the edible oil is canola oil. In some embodiments, theedible oil is peanut oil. In some embodiments, the edible oil comprisesone or more a nut oils. In some embodiments, the nut oil is selectedfrom the group consisting of almond oil, cashew oil, hazelnut oil,macadamia oil, mongongo nut oil, pecan oil, pine nut oil, pistachio oil,walnut oil, and mixtures thereof. The edible oil can also comprise amixture of vegetable oils and nut oils, as appropriate or desired.

In some embodiments, the composition comprises or consists essentiallyof allopregnanolone and canola oil. In some embodiments, the compositioncomprises or consists essentially of allopregnanolone and peanut oil.

In some embodiments, the composition is contained within a soft gelcapsule for oral delivery to a subject.

In a further aspect, the invention provides methods of treating,reducing, and/or mitigating symptoms associated with and/or caused bytraumatic brain injury, Alzheimer's disease, epilepsy, anxiety, fragileX syndrome, post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, andsmoking cessation in a subject in need thereof, comprisingadministration to the subject orally or transmucosally a composition asdescribed above and herein. In some embodiments, the composition isadministered orally.

In a related aspect, the invention provides methods of treating,reducing, and/or mitigating symptoms associated with and/or caused byepilepsy, in a subject in need thereof, comprising administration to thesubject orally or transmucosally a composition as described above andherein. In a further aspect, the invention provides methods ofaccelerating the termination or abortion of an impending seizure in asubject in need thereof, comprising administration to the subject orallyor transmucosally a composition as described above and herein. In someembodiments, the subject is experiencing aura. In some embodiments, thesubject has been warned of an impending seizure. In some embodiments,the subject is experiencing a seizure. In some embodiments, the subjecthas status epilepticus. In some embodiments, the subject has myoclonicepilepsy. In some embodiments, the subject suffers from seizureclusters. In some embodiments, the seizure is a tonic seizure. In someembodiments, the seizure is a clonic seizure.

Definitions

As used herein, “administering” refers to oral (“po”) administration andtransmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal)delivery.

The term “co-administration” refers to the presence of both activeagents in the blood at the same time. Active agents that areco-administered can be delivered concurrently (i.e., at the same time)or sequentially.

The phrase “cause to be administered” refers to the actions taken by amedical professional (e.g., a physician), or a person controllingmedical care of a subject, that control and/or permit the administrationof the agent(s)/compound(s) at issue to the subject. Causing to beadministered can involve diagnosis and/or determination of anappropriate therapeutic or prophylactic regimen, and/or prescribingparticular agent(s)/compounds for a subject. Such prescribing caninclude, for example, drafting a prescription form, annotating a medicalrecord, and the like.

The term “effective amount” or “pharmaceutically effective amount” referto the amount and/or dosage, and/or dosage regime of one or morecompounds necessary to bring about the desired result e.g., an amountsufficient prevent, abort or terminate a seizure.

As used herein, the terms “treating” and “treatment” refer to delayingthe onset of, retarding or reversing the progress of, reducing theseverity of, or alleviating or preventing either the disease orcondition to which the term applies, or one or more symptoms of suchdisease or condition.

The terms “reduce,” “inhibit,” “relieve,” “alleviate” refer to thedetectable decrease in the frequency, severity and/or duration ofseizures. A reduction in the frequency, severity and/or duration ofseizures can be measured by self-assessment (e.g., by reporting of thepatient) or by a trained clinical observer. Determination of a reductionof the frequency, severity and/or duration of seizures can be made bycomparing patient status before and after treatment.

The term “mitigating” refers to reduction or elimination of one or moresymptoms of that pathology or disease, and/or a reduction in the rate ordelay of onset or severity of one or more symptoms of that pathology ordisease, and/or the prevention of that pathology or disease.

As used herein, the phrase “consisting essentially of” refers to thegenera or species of active pharmaceutical agents (e.g., neurosteroid,e.g., allopregnanolone) and excipient (e.g., edible oil) included in amethod or composition. In various embodiments, other unmentioned orunrecited active ingredients and inactive are expressly excluded. Invarious embodiments, additives (e.g., surfactants, acids (organic orfatty), alcohols, esters, co-solvents, solubilizers, lipids, polymers,glycols) are expressly excluded.

The terms “subject,” “individual,” and “patient” interchangeably referto a mammal, preferably a human or a non-human primate, but alsodomesticated mammals (e.g., canine or feline), laboratory mammals (e.g.,mouse, rat, rabbit, hamster, guinea pig) and agricultural mammals (e.g.,equine, bovine, porcine, ovine). In various embodiments, the subject canbe a human (e.g., adult male, adult female, adolescent male, adolescentfemale, male child, female child) under the care of a physician or otherhealthworker in a hospital, psychiatric care facility, as an outpatient,or other clinical context. In certain embodiments the subject may not beunder the care or prescription of a physician or other healthworker.

The term “edible oil” refers to an oil that is digestible by a mammal.Preferred oils are edible or digestible without inducing undesirableside effects.

The term “neuroactive steroid” or “neurosteroid” refers to steroidcompounds that rapidly alter neuronal excitability through interactionwith neurotransmitter-gated ion channels. Neurosteroids act asallosteric modulators of neurotransmitter receptors, such as GABA_(A),NMDA, and sigma receptors. Neurosteroids find use as sedatives for thepurpose of general anaesthesia for carrying out surgical procedures, andin the treatment of epilepsy and traumatic brain injury. Illustrativeneurosteroids include, e.g., allopregnanolone, Ganaxolone, alphaxolone,alphadolone, hydroxydione, minaxolone, and Althesin (a mixture ofalphaxolone and alphadolone).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates time course of allopregnanolone (ALP) activity whenadministered in a canola oil vehicle to mice by oral gavage.

FIG. 2 illustrates time course of ganaxolone (GNX) activity whenadministered in a canola oil vehicle to mice by oral gavage.

FIG. 3 illustrates a comparison of sedation activity of ALP administeredto mice in a canola oil vehicle versus ALP administered to mice in aTween-80 vehicle.

FIG. 4 illustrates that oral delivery of allopregnanolone in canola oilmarkedly enhances the oral bioavailability of allopregnanolone. Thisexperiment presents a practical approach developed for oral delivery ofallopregnanolone. The effective threshold dose was between 25-75 mg/kg.This is a practical dose.

FIG. 5 illustrates a vehicle comparison for anticonvulsant activity ofALP orally delivered in a canola oil vehicle versus ALP administered tomice in a Tween-80 vehicle.

FIG. 6 illustrates a comparison the anticonvulsant activity of orallyadministered allopregnanolone solubilized by three different oils in thePTZ seizure threshold test. Allopregnanolone dissolved in miglyol wasinactive at a dose of 100 mg/kg. In contrast, when dissolved in eithercanola oil or peanut oil, allopregnanolone at doses of 50 mg/kg (5mg/ml) and 100 mg/kg (10 mg/ml) caused a time-dependent increase inseizure threshold. The abscissa indicates the time between oral dosingof allopregnanolone or vehicle and the onset of the intravenous PTZinfusion. Each bar represents the mean±S.E.M. of the threshold valuesfor 6-9 mice. *, p<0.05 compared with vehicle-treated control group(t-test).

FIG. 7 illustrates a time course for seizure protection in the 6-Hz testproduced by allopregnanolone (200 mg/kg) dissolved in canola oil (10mg/ml). The 6-Hz electrical stimulation was delivered at 32 mA for 3 s.The interval between the steroid injection and the electrical stimulusis plotted on the abscissa and the percentage of animals protectedagainst seizures is plotted on the ordinate. Each point represents 8mice.

DETAILED DESCRIPTION

1. Introduction

The present invention is based, in part, on the discovery that edibleoils (e.g., including without limitation peanut oil, canola oil, oliveoil) markedly enhance the absorption of steroids, includingneurosteroids (e.g., allopregnanolone) delivered to a patient via theoral route. Suspending or dissolving steroids in an edible oil presentsa practical and efficacious method of administering steroids, includingneurosteroids (e.g., allopregnanolone), to a patient. Largeconcentrations of steroids can be carried in a relatively small volumeof oil. Therefore, the volume necessary to deliver an equivalent amountof steroid is much smaller when formulated in an edible oil carrier thanwhen formulated in an aqueous solution carrier (e.g., using asolubilizer cyclodextrin solution). Steroids, and particularlyneurosteroids, have poor bioavailability when administered orally.Therefore, large amounts must be administered to achieve satisfactoryexposure. It is oftentimes impractical to deliver such large amounts(e.g., because each dose requires many pills or excessively large pillsthat are difficult to swallow) and the cost of goods may be prohibitive.

Surprisingly, the absorption and delivery to the brain of neurosteroids,including allopregnanolone, can be promoted or increased when thesteroid is suspended or dissolved in an edible oil. Formulation in anedible oil allows for the practical and efficacious delivery ofsteroids, including neurosteroids (e.g., allopregnanolone) orally. Invarious embodiments, the steroid, including neurosteroids (e.g.,allopregnanolone) dissolved or suspended in an edible oil can beadministered in a gelatin capsule, e.g., produced by soft-gelencapsulation technology. For example, parenteral administration ofallopregnanolone as an aqueous solution inhydroxypropyl-beta-cyclodextrin, readily causes central nervous systemeffects. By comparison, even high doses of allopregnanolone administeredorally in an aqueous solution, such as in an aqueous solution ofhydroxyproply-beta-cyclodextrin, failed to produce central nervoussystem effects. However, allopregnanolone at doses of 250 mg/kg incanola oil, produces profound sedation and anticonvulsant activity inthe pentylenetetrazol seizure test, demonstrating that theallopregnanolone formulated in the edible oil is absorbed.

2. Subjects Who can Benefit

In various embodiments, the subject has a condition that can be treatedor mitigated by administration of a neurosteroid, e.g.,allopregnanolone. Allopregnanolone has many medical uses, including thetreatment, reduction, and/or mitigation of symptoms associated withand/or caused by traumatic brain injury, Alzheimer's disease, epilepsy,anxiety, fragile X syndrome, post-traumatic stress disorder, lysosomalstorage disorders (Niemann-Pick type C disease), depression (includingpost-partum depression), premenstrual dysphoric disorder, alcoholcraving, and smoking cessation. The subject may or may not be exhibitingsymptoms.

Accordingly, the invention also contemplates methods of treating,reducing, and/or mitigating symptoms associated with and/or caused bytraumatic brain injury, Alzheimer's disease, epilepsy, anxiety, fragileX syndrome, post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, andsmoking cessation by administration of a steroid or neurosteroid (e.g.,allopregnanolone) dissolved or suspended in an edible oil, as describedherein.

In some embodiments, the subject has epilepsy, has a history ofsuffering from epileptic seizures or is suffering from epilepticseizures. In various embodiments, the patient may be experiencing anelectrographic or behavioral seizure or may be experiencing a seizureaura, which itself is a localized seizure that may spread and become afull blown behavioral seizure. For example, the subject may beexperiencing aura that alerts of the impending onset of a seizure orseizure cluster.

Alternatively, the subject may be using a seizure prediction device thatalerts of the impending onset of a seizure or seizure cluster.Implantable seizure prediction devices are known in the art anddescribed, e.g., in D'Alessandro, et al., IEEE TRANSACTIONS ONBIOMEDICAL ENGINEERING, VOL. 50, NO. 5, May 2003, and U.S. PatentPublication Nos. 2010/0198098, 2010/0168603, 2009/0062682, and2008/0243022.

The subject may have a personal or familial history of any of theepileptic conditions described herein. The subject may have beendiagnosed as having any of the epileptic conditions described herein. Insome embodiments, the subject has or is at risk of suffering a myoclonicseizure or myoclonic epilepsy, e.g., juvenile myoclonic epilepsy. ThePTZ seizure model demonstrated herein is predictive of utility and/oractivity in counteracting myoclonic seizures or myoclonic epilepsy inhumans.

In various embodiments, the subject may be at risk of exposure to or mayhave been exposed to a nerve agent or a pesticide that can causeseizures. Illustrative nerve agents that can cause seizures include,e.g., organophosphorus nerve agents, e.g., tabun, sarin, soman, GF, VRand/or VX. Illustrative pesticides that can cause seizures include,e.g., organophosphate pesticides (e.g., Acephate (Orthene),Azinphos-methyl (Gusathion, Guthion), Bensulide (Betasan, Lescosan),Bomyl (Swat), Bromophos (Nexion), Bromophos-ethyl (Nexagan), Cadusafos(Apache, Ebufos, Rugby), Carbophenothion (Trithion), Chlorethoxyfos(Fortress), Chlorfenvinphos (Apachlor, Birlane), Chlormephos (Dotan),Chlorphoxim (Baythion-C), Chlorpyrifos (Brodan, Dursban, Lorsban),Chlorthiophos (Celathion), Coumaphos (Asuntol, Co-Ral), Crotoxyphos(Ciodrin, Cypona), Crufomate (Ruelene), Cyanofenphos (Surecide),Cyanophos (Cyanox), Cythioate (Cyflee, Proban), DEF (De-Green), E-Z-OffD), Demeton (Systox), Demeton-S-methyl (Duratox, Metasystoxl), Dialifor(Torak), Diazinon, Dichlorofenthion, (VC-13 Nemacide), Dichlorvos (DDVP,Vapona), Dicrotophos (Bidrin), Dimefos (Hanane, Pestox XIV), Dimethoate(Cygon, DeFend), Dioxathion (Delnav), Disulfoton (Disyston), Ditalimfos,Edifenphos, Endothion, EPBP (S-seven), EPN, Ethion (Ethanox), Ethoprop(Mocap), Ethyl parathion (E605, Parathion, thiophos), Etrimfos (Ekamet),Famphur (Bash, Bo-Ana, Famfos), Fenamiphos (Nemacur), Fenitrothion(Accothion, Agrothion, Sumithion), Fenophosphon (Agritox,trichloronate), Fensulfothion (Dasanit), Fenthion (Baytex, Entex,Tiguvon), Fonofos (Dyfonate, N-2790), Formothion (Anthio), Fosthietan(Nem-A-Tak), Heptenophos (Hostaquick), Hiometon (Ekatin), Hosalone(Zolone), IBP (Kitazin), Iodofenphos (Nuvanol-N), Isazofos (Brace,Miral, Triumph), Isofenphos (Amaze, Oftanol), Isoxathion (E-48,Karphos), Leptophos (Phosvel), Malathion (Cythion), Mephosfolan(Cytrolane), Merphos (Easy Off-D, Folex), Methamidophos (Monitor),Methidathion (Supracide, Ultracide), Methyl parathion (E601, Penncap-M),Methyl trithion, Mevinphos (Duraphos, Phosdrin), Mipafox (Isopestox,Pestox XV), Monocrotophos (Azodrin), Naled (Dibrome), Oxydemeton-methyl(Metasystox-R), Oxydeprofos (Metasystox-S), Phencapton (G 28029),Phenthoate (Dimephenthoate, Phenthoate), Phorate (Rampart, Thimet),Phosalone (Azofene, Zolone), Phosfolan (Cylan, Cyolane), Phosmet(Imidan, Prolate), Phosphamidon (Dimecron), Phostebupirim (Aztec),Phoxim (Baythion), Pirimiphos-ethyl (Primicid), Pirimiphos-methyl(Actellic), Profenofos (Curacron), Propetamphos (Safrotin), Propylthiopyrophosphate (Aspon), Prothoate (Fac), Pyrazophos (Afugan,Curamil), Pyridaphenthion (Ofunack), Quinalphos (Bayrusil), Ronnel(Fenchlorphos, Korlan), Schradan (OMPA), Sulfotep (Bladafum, Dithione,Thiotepp), Sulprofos (Bolstar, Helothion), Temephos (Abate, Abathion),Terbufos (Contraven, Counter), Tetrachlorvinphos (Gardona, Rabon),Tetraethyl pyrophosphate (TEPP), Triazophos (Hostathion), andTrichlorfon (Dipterex, Dylox, Neguvon, Proxol).

3. Steroids

The compositions generally comprise or consist essentially of a steroid,e.g., a neurosteroid, suspended or dissolved in an edible oil.

In various embodiments the neurosteroid is allopregnanolone (ALP).Allopregnanolone, also known as 3a-hydroxy-5a-pregnan-20-one or3α,5α-tetrahydroprogesterone, IUPAC name1-(3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone,and referenced as CAS number 516-54-1, is a prototypic neurosteroidpresent in the blood and also the brain. It is a metabolite ofprogesterone and modulator of GABA_(A) receptors. Whileallopregnanolone, like other GABA_(A) receptor active neurosteroids suchas allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one;THDOC), positively modulates all GABA_(A) receptor isoforms, thoseisoforms containing δ-subunits exhibit greater magnitude potentiation.Allopregnanolone has pharmacological properties similar to otherpositive modulators of GABA_(A) receptors, including anxiolytic andanticonvulsant activity. Allopregnanolone is neuroprotective in manyanimal models of neurodegenerative conditions, including, e.g.,Alzheimer's disease (Wang et al., Proc Natl Acad Sci USA. 2010 Apr. 6;107(14):6498-503), cerebral edema (Limmroth et al., Br J Pharmacol. 1996January; 117(1):99-104) and traumatic brain injury (He et al., RestorNeurol Neurosci. 2004; 22(1):19-31; and He, et al., Exp Neurol. 2004October; 189(2):404-12), Mood disorders (Robichaud and Debonnel, Int JNeuropsychopharmacol. 2006 April; 9(2):191-200), Niemann-Pick type Cdisease (Griffin et al., Nat Med. 2004 July; 10(7):704-11) and acts asan anticonvulsant against chemically induced seizures, including thepentylenetetrazol (PTZ) model (Kokate et al., J Pharmacol Exp Ther. 1994Sep.; 270(3):1223-9). The chemical structure of allopregnanolone isdepicted below in Formula I:

In various embodiments, the compositions comprise a sulfate, salt,hemisuccinate, nitrosylated, derivative or congener of allopregnanolone.

Delivery of other neurosteroids also can be enhanced by formulation inan edible oil. Other neurosteroids that can be formulated in an edibleoil, include without limitation allotetrahydrodeoxycorticosterone(3α,21-dihydroxy-5α-pregnan-20-one; THDOC),3α,21-dihydroxy-5b-pregnan-20-one, pregnanolone(3α-hydroxy-5β-pregnan-20-one), Ganaxolone (INN, also known as CCD-1042;IUPAC name (3α,5α)-3-hydroxy-5-methylpregnan-20-one;1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone),alphaxolone, alphadolone, hydroxydione, minaxolone, and Althesin (amixture of alphaxolone, alphadolone, tetrahydrodeoxycorticosterone,pregnenolone, dehydroepiandrosterone (DHEA), 7-substitutedbenz[e]indene-3-carbonitriles (see, e.g., Hu, et al., J Med Chem. (1993)36(24):3956-67); 7-(2-hydroxyethyl)benz[e]indene analogues (see, e.g.,Han, et al., J Med Chem. (1995) 38(22):4548-56); 3 alpha-hydroxy-5alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one analogues(see, e.g., Han, et al., J Med Chem. (1996) 39(21):4218-32); enantiomersof dehydroepiandrosterone sulfate, pregnenolone sulfate, and(3alpha,5beta)-3-hydroxypregnan-20-one sulfate (see, e.g., Nilsson, etal., J Med Chem. (1998) 41(14):2604-13); 13,24-cyclo-18,21-dinorcholaneanalogues (see, e.g., Jiang, et al., J Med Chem. (2003) 46(25):5334-48);N-acylated 17a-aza-D-homosteroid analogues (see, e.g., Covey, et al., JMed Chem. (2000) 43(17):3201-4); 5 beta-methyl-3-ketosteroid analogues(see, e.g., Zeng, et al., J Org Chem. (2000) 65(7):2264-6);18-norandrostan-17-one analogues (see, e.g., Jiang, et al., J Org Chem.(2000) 65(11):3555-7); (3alpha,5alpha)- and(3alpha,5beta)-3-hydroxypregnan-20-one analogs (see, e.g., Zeng, et al.,J Med Chem. (2005) 48(8):3051-9); benz[f]indenes (see, e.g., Scaglione,et al., J Med Chem. (2006) 49(15):4595-605); enantiomers of androgens(see, e.g., Katona, et al., Eur J Med Chem. (2008) 43(1):107-13);cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes (see, e.g.,Scaglione, et al., J Med Chem. (2008) 51(5):1309-18);2beta-hydroxygonane derivatives (see, e.g., Wang, et al., Tetrahedron(2007) 63(33):7977-7984); Δ16-alphaxalone and corresponding17-carbonitrile analogues (see, e.g., Bandyopadhyaya, et al., Bioorg MedChem Lett. (2010) 20(22):6680-4); 4(16) and 4(17(20)) analogues ofΔ(16)-alphaxalone (see, e.g., Stastna, et al., J Med Chem. (2011)54(11):3926-34); neurosteroid analogs developed by CoCensys (now PurdueNeuroscience) (e.g., CCD-3693, Co2-6749 (a.k.a., GMA-839 andWAY-141839); neurosteroid analogs described in U.S. Pat. No. 7,781,421and in PCT Patent Publications WO 2008/157460; WO 1993/003732; WO1993/018053; WO 1994/027608; WO 1995/021617; WO 1996/016076; WO1996/040043, as well as salts, hemisuccinates, nitrosylated, sulfatesand derivatives thereof.

In various embodiments, the steroid or neurosteroid is not a sexhormone. In various embodiments, the steroid or neurosteroid is notprogesterone.

As appropriate, the steroid or neurosteroid (e.g., allopregnanolone) mayor may not be micronized. As appropriate, the steroid or neurosteroid(e.g., allopregnanolone) may or may not be enclosed in microspheres insuspension in the oil.

4. Edible Oils

The steroid or neurosteroid is dissolved or suspended in an oil that isedible and/or digestible by the subject, e.g., without undesirable sideeffects.

In various embodiments, the edible oil comprises one or more vegetableoils. In various embodiments, the vegetable oil is selected from thegroup consisting of coconut oil, corn oil, cottonseed oil, olive oil,palm oil, peanut oil, rapeseed oil, canola oil, safflower oil, sesameoil, soybean oil, sunflower oil, and mixtures thereof.

In some embodiments, the edible oil comprises one or more nut oils. Insome embodiments, the nut oil is selected from the group consisting ofalmond oil, cashew oil, hazelnut oil, macadamia oil, mongongo nut oil,pecan oil, pine nut oil, pistachio oil, walnut oil, and mixturesthereof.

In some embodiments, the edible oil does not comprise castor oil. Insome embodiments, the edible oil does not comprise peanut oil.

Generally, the oils used in the present compositions are isolated fromthe source, e.g., plant, and used without including further additives(e.g., surfactants, acids (organic or fatty), alcohols, esters,co-solvents, solubilizers, lipids, polymers, glycols) or processing. Invarious embodiments, the oil vehicle further comprises a preservative(e.g., vitamin E).

5. Formulation and Administration

The oil-steroid compositions can be formulated for oral and/ortransmucosal delivery using any method known in the art. In oneembodiment, the oil-steroid composition is formulated in a capsule,e.g., for oral delivery.

a. Capsules

The capsule shells can be prepared using one or more film formingpolymers. Suitable film forming polymers include natural polymers, suchas gelatin, and synthetic film forming polymers, such as modifiedcelluloses. Suitable modified celluloses include, but are not limitedto, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulosephthalate, and cellulose acetate phthalate. Hard or soft capsules can beused to administer the hormone. Hard shell capsules are typicallyprepared by forming the two capsule halves, filling one of the halveswith the fill solution, and then sealing the capsule halves together toform the finished capsule. Soft gelatin capsules are typically preparedusing a rotary die encapsulation process as described below.

i. Gelatin Capsules

Gelatin is the product of the partial hydrolysis of collagen. Gelatin isclassified as either Type A or Type B gelatin. Type A gelatin is derivedfrom the acid hydrolysis of collagen while Type B gelatin is derivedfrom the alkaline hydrolysis of collagen. Traditionally, bovine bonesand skins have been used as raw materials for manufacturing Type A andType B gelatin while porcine skins have been used extensively formanufacturing Type A gelatin. In general, acid-processed gelatins formstronger gels than lime-processed gelatins of the same average molecularweight. The capsules can be formulated as hard or soft gelatin capsules.

ii. Non-Gelatin Capsules

Capsules can be prepared from non-gelatin materials, such as carrageenanor modified celluloses. Carrageenan is a natural polysaccharidehydrocolloid, which is derived from seaweed. It includes a linearcarbohydrate polymer of repeating sugar units, without a significantdegree of substitution or branching. Most, if not all, of the galactoseunits on a carrageenan molecule possess a sulfate ester group. There arethree main types of carrageenan: kappa, iota and lambda; although minorforms called mu and nu carrageenan also exist.

iii. Shell Additives

Suitable shell additives include plasticizers, opacifiers, colorants,humectants, preservatives, flavorings, and buffering salts and acids,and combinations thereof.

Plasticizers are chemical agents added to gelatin to make the materialsofter and more flexible. Suitable plasticizers include, but are notlimited to, glycerin, sorbitol solutions which are mixtures of sorbitoland sorbitan, and other polyhydric alcohols such as propylene glycol andmaltitol or combinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulatedactive agents are light sensitive. Suitable opacifiers include titaniumdioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used for marketing and productidentification/differentiation purposes. Suitable colorants includesynthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel.Suitable humectants include glycerin and sorbitol, which are oftencomponents of the plasticizer composition. Due to the low water activityof dried, properly stored softgels, the greatest risk frommicroorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into the capsule shell. Suitablepreservatives include alkyl esters of p-hydroxy benzoic acid such asmethyl, ethyl, propyl, butyl and heptyl esters (collectively known as“parabens”) or combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fillformulations. Suitable flavorings include synthetic and naturalflavorings. The use of flavorings can be problematic due to the presenceof aldehydes which can cross-link gelatin. As a result, buffering saltsand acids can be used in conjunction with flavorings that containaldehydes in order to inhibit cross-linking of the gelatin.

b. Enteric Capsules

Alternatively, the liquid fills can be incorporated into an entericcapsule, wherein the enteric polymer is a component of the capsuleshell, as described in WO 2004/030658 to Banner Pharmacaps, Inc. Theenteric capsule shell is prepared from a mass comprising a film-formingpolymer, an acid-insoluble polymer which is present in an amount makingthe capsule resistant to the acid within the stomach, an aqueoussolvent, and optionally, one or more plasticizers and/or colorants.Other suitable shell additives including opacifiers, colorants,humectants, preservatives, flavorings, and buffering salts and acids maybe added.

i. Film-Forming Polymers

Exemplary film-forming polymers can be of natural or synthetic origin.Natural film-forming polymers include gelatin and gelatin-like polymers.Other suitable natural film-forming polymers include shellac, alginates,pectin, and zeins. Synthetic film-forming polymers include hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose phthalate, celluloseacetate phthalate, and acrylates such as poly (meth)acrylate. The weightratio of acid-insoluble polymer to film-forming polymer is from about15% to about 50%. In one embodiment, the film forming polymer isgelatin.

ii. Acid-Insoluble Polymers

Exemplary acid-insoluble polymers include cellulose acetate phthalate,cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate,algenic acid salts such as sodium or potassium alginate, shellac,pectin, acrylic acid-methylacrylic acid copolymers (available under thetradename EUDRAGIT® from Rohm America Inc., Piscataway, N.J. as a powderor a 30% aqueous dispersion; or under the tradename EASTACRYL®, fromEastman Chemical Co., Kingsport, Tenn., as a 30% dispersion). In oneembodiment, the acid-insoluble polymer is EUDRAGIT® L100, which is amethacrylic acid/methacrylic acid methyl ester copolymer. Theacid-insoluble polymer is present in an amount from about 8% to about20% by weight of the wet gelatin mass. The weight ratio ofacid-insoluble polymer to film-forming polymer is from about 15% toabout 50%.

iii. Aqueous Solvent

Hard and soft capsules are typically prepared from solutions orsuspensions of the film forming polymer and the acid-insoluble polymer.Suitable solvents include water, aqueous solvents, and organic solvents.In one embodiment, the solvent is water or an aqueous solvent. Exemplaryaqueous solvents include water or aqueous solutions of alkalis such asammonia, sodium hydroxide, potassium hydroxide, ethylene diamine,hydroxylamine, tri-ethanol amine, or hydroalcoholic solutions of thesame. The alkali can be adjusted such that the final pH of the gelatinmass is less than or equal to 9.0, preferably less than or equal to 8.5,more preferably less than or equal to 8.0. In one embodiment, the alkaliis a volatile alkali such as ammonia or ethylene diamine. Upon drying ofthe finished capsule, the water content of the capsule is from about 2%to about 10% by weight of the capsule, preferably from about 4% to about8% by weight of the capsule.

iv. Plasticizers

Exemplary plasticizers include glycerol, glycerin, sorbitol,polyethylene glycol, citric acid, citric acid esters such astriethylcitrate, polyalcohols with 3-6 carbons and combinations thereof.The plasticizer to polymer (film forming polymer plus acid-insolublepolymer) ratio is from about 10% to about 50% of the polymer weight.

c. Methods of Manufacture

i. Capsule Fill

The fill material is prepared by dissolving the steroid or neurosteroid(e.g., allopregnanolone) in the carrier containing a fatty acid solvent,such as oleic acid. The mixture of hormone and fatty acid may be heatedto facilitate dissolution of the hormone. Upon cooling to roomtemperature and encapsulation, the solution remains a liquid. The fillis typically deaerated prior to encapsulation in a soft gelatin capsule.Additional excipients including, but not limited to, co-solvents,antioxidants may be added to the mixture of the hormone and fatty acid.Again the mixture may be heated to facilitate dissolution of theexcipients. The steroid or neurosteroid (e.g., allopregnanolone) isfully dissolved in the carrier of the present invention and remains soupon storage.

i. Capsule Shell

A. Gelatin or Non-Gelatin Capsules

The main ingredients of the capsule shell are gelatin (or a gelatinsubstitute for non-gelatin capsules), plasticizer, and purified water.The primary difference between soft and hard capsules is the amount ofplasticizer present in the capsule shell.

Typical gel formulations contain (w/w) 40-50% gelatin, 20-30%plasticizer, and 30-40% purified water. Most of the water issubsequently lost during capsule drying. The ingredients are combined toform a molten gelatin mass using either a cold melt or a hot meltprocess. The prepared gel masses are transferred to preheated,temperature-controlled, jacketed holding tanks where the gel mass isaged at 50-60° C. until used for encapsulation.

i. Cold Melt Process

The cold melt process involves mixing gelatin with plasticizer andchilled water and then transferring the mixture to a jacket-heated tank.Typically, gelatin is added to the plasticizer at ambient temperature(18-22° C.). The mixture is cooked (57-95° C.) under vacuum for 15-30minutes to a homogeneous, deaerated gel mass. Additional shell additivescan be added to the gel mass at any point during the gel manufacturingprocess or they may be incorporated into the finished gel mass using ahigh torque mixer.

ii. Hot Melt Process

The hot melt process involves adding, under mild agitation, the gelatinto a preheated (60-80° C.) mixture of plasticizer and water and stirringthe blend until complete melting is achieved. While the hot melt processis faster than the cold melt process, it is less accurately controlledand more susceptible to foaming and dusting.

b. Soft Capsules

Soft capsules are typically produced using a rotary die encapsulationprocess. The gel mass is fed either by gravity or through positivedisplacement pumping to two heated (48-65° C.) metering devices. Themetering devices control the flow of gel into cooled (10-18° C.),rotating casting drums. Ribbons are formed as the cast gel masses set oncontact with the surface of the drums.

The ribbons are fed through a series of guide rolls and betweeninjection wedges and the capsule-forming dies. A food-grade lubricantoil is applied onto the ribbons to reduce their tackiness and facilitatetheir transfer. Suitable lubricants include mineral oil, medium chaintriglycerides, and soybean oil. Fill formulations are fed into theencapsulation machine by gravity. In the preferred embodiment, the softcapsules contain printing on the surface, optionally identifying theencapsulated agent and/or dosage.

Upon drying of the finished capsule, the water content of the capsule isfrom about 2% to about 10% by weight of the capsule, preferably fromabout 4% to about 8% by weight of the capsule.

c. Enteric Capsules

A method of making an enteric capsule shell is described in WO2004/030658 to Banner Pharmacaps, Inc. The enteric mass is typicallymanufactured by preparing an aqueous solution comprising a film-forming,water soluble polymer and an acid-insoluble polymer and mixing thesolution with one or more appropriate plasticizers to form a gelatinmass. Alternatively, the enteric mass can be prepared by using aready-made aqueous dispersion of the acid-insoluble polymer by addingalkaline materials such as ammonium, sodium, or potassium hydroxides orother alkalis that will cause the acid-insoluble polymer to dissolve.The plasticizer-wetted, film-forming polymer can then be mixed with thesolution of the acid-insoluble polymer. The mass can also be prepared bydissolving the acid-insoluble polymer or polymers in the form of saltsof the above-mentioned bases or alkalis directly in water and mixing thesolution with the plasticizer-wetted, film-forming polymer. The mass iscast into films or ribbons using heat controlled drums or surfaces. Thefill material is encapsulated in a soft capsule using a rotary die. Thecapsules are dried under controlled conditions of temperature andhumidity. The final moisture content of the shell composition is fromabout 2% to about 10% by weight of the capsule shell, preferably fromabout 4% to about 8% by weight by weight of the capsule shell.

Alternatively, release of the steroid or neurosteroid (e.g.,allopregnanolone) from the capsule can be modified by coating thecapsule with one or more modified release coatings, such as sustainedrelease coatings, delayed release coatings, and combinations thereof.

The concentration of the steroid or neurosteroid (e.g.,allopregnanolone) in the edible oil vehicle is preferably in unit dosageform. The term “unit dosage form”, as used in the specification, refersto physically discrete units suitable as unitary dosages for humansubjects and animals, each unit containing a predetermined quantity ofactive material calculated to produce the desired pharmaceutical effectin association with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the active material and the particular effect to beachieved and (b) the limitations inherent in the art of compounding suchan active material for use in humans and animals, as disclosed in detailin this specification, these being features of the present invention.

Determination of an effective amount for administration in a singledosage is well within the capability of those skilled in the art,especially in light of the detailed disclosure provided herein.Generally, an efficacious or effective amount of the steroid orneurosteroid (e.g., allopregnanolone) is determined by firstadministering a low dose or small amount of the agent and thenincrementally increasing the administered dose or dosages, adding asecond or third medication as needed, until a desired effect of isobserved in the treated subject with minimal or no toxic side effects.Applicable methods for determining an appropriate dose and dosingschedule for administration of a combination of the present inventionare described, for example, in Goodman and Gilman's The PharmacologicalBasis of Therapeutics, 12th Edition, 2010, supra; in a Physicians' DeskReference (PDR), 65^(th) Edition, 2011; in Remington: The Science andPractice of Pharmacy, 21^(st) Ed., 2005, supra; and in Martindale: TheComplete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press.,and in Martindale, Martindale: The Extra Pharmacopoeia, 31st Edition.,1996, Amer Pharmaceutical Assn, each of which are hereby incorporatedherein by reference. In various embodiments, the compositions areformulated for administration of about 5 mg/kg to about 50 mg/kg of thesteroid or neurosteroid (e.g., allopregnanolone), e.g., about 5 mg/kg,10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45mg/kg, or 50 mg/kg.

6. Monitoring Efficacy

In various embodiments, administration of a steroid or neurosteroid(e.g., allopregnanolone) to a subject results in the prevention ormitigation of one or more symptoms of the disease condition beingtreated (e.g., traumatic brain injury, Alzheimer's disease, epilepsy,anxiety, fragile X syndrome, post-traumatic stress disorder, lysosomalstorage disorders (Niemann-Pick type C disease), depression (includingpost-partum depression), premenstrual dysphoric disorder, alcoholcraving, and smoking cessation). Symptoms of disease can be comparedbefore and after administration of a steroid or neurosteroid (e.g.,allopregnanolone) to the subject. Administration of the steroid orneurosteroid (e.g., allopregnanolone) to the subject is considered to beeffective if the symptoms no longer occur after administration (e.g.,seizures), or if the symptoms are reduced, alleviated and/or mitigatedafter administration.

In various embodiments, administration of a steroid or neurosteroid(e.g., allopregnanolone) to a subject results in the prevention of theoccurrence of an impending seizure and/or the termination or abortion ofa seizure in progress.

In various embodiments, efficacy can be monitored by the subject. Forexample, in a subject experiencing aura or receiving a warning from aseizure prediction device, the subject can self-administer a dose of thesteroid or neurosteroid (e.g., allopregnanolone). If the steroid orneurosteroid (e.g., allopregnanolone) is administered in an efficaciousamount, the sensation of aura should subside and/or the seizureprediction device should no longer predict the imminent occurrence of animpending seizure. If the sensation of aura does not subside and/or theseizure prediction device continues to predict an impending seizure, asecond dose of steroid or neurosteroid (e.g., allopregnanolone) can beadministered.

In other embodiments, the efficacy is monitored by a caregiver. Forexample, in a subject experiencing the onset of a seizure or insituations where a seizure has commenced, the subject may requireadministration of the steroid or neurosteroid (e.g., allopregnanolone)by a caregiver. If the steroid or neurosteroid (e.g., allopregnanolone)is administered in an efficacious amount, the seizure, along with thesubject's symptoms of the seizure, should terminate or abort. If theseizure does not terminate, a second dose of the steroid or neurosteroid(e.g., allopregnanolone) can be administered.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1

NIH Swiss mice were fasted 2 hours prior to experiment participation.Allopregnanolone (ALP) was suspended in vehicle (Tween 80 or canolaoil). The time point of maximal effect of ALP was established bygavaging ALP and scoring relevant behavioral parameters outlined in theIrwin Test. See, Sylvain Roux, et al., Current Protocols inPharmacology, Unit Number: UNIT 10.10, DOI: 10.1002/0471141755.ph1010s27Online Posting Date: January, 2005. Lethality, convulsion, tremor,Straub, abnormal gait, fear, sedation, reactivity to touch, loss oftraction, loss of righting reflex were measured.

Anticonvulsant potential of ALP was determined with PTZ seizurechallenge. Oral gavage various ALP concentrations at 50 μl/10 g bodyweight, t=−45 min or t=−90 min, 80 mg/kg PTZ s.c. at t=0. Observe 30 minfor seizure protection (absence of clonic spasms).

Example 2 Methods

Animals.

Male NIH Swiss mice (22-30 g) were housed four per cage. Animals werekept in a vivarium under controlled laboratory conditions (temperature,22-26° C.; humidity, 40-50%) with an artificial 12-h light/dark cycleand free access to food and water. Animals were allowed to acclimate tothe vivarium for ≥5 days. The experiments were performed during thelight phase of the light/dark cycle after a ≥30-min period ofacclimation to the experimental room. Animals were maintained infacilities fully accredited by the Association for Assessment andAccreditation of Laboratory Animal Care, and all studies were performedunder protocols approved by the University of California, Davis,Institutional Animal Care and Use Committee the Animal Care and Use instrict compliance with the Guide for the Care and Use of LaboratoryAnimals of the National Research Council (National Academy Press,Washington, D.C.; on the internet atnap.edu/readingroom/books/labrats/).

Test Substances and Drug Administration.

Solutions of allopreganolone (SAFC Pharma, Madison, Wis., U.S.A.) weremade in miglyol (Neobee M5®, Spectrum Chemicals, Gardena, Calif.),canola oil (ConAgra Foods, Omaha, Nebr.) or peanut oil (Sigma-Aldrich,St. Louis, Mo.). The convulsant agent pentylenetetrazol (PTZ)(Sigma-Aldrich, St. Louis, Mo.) was dissolved in saline immediatelybefore use and administered intravenously (i.v.). For the PTZ thresholdtest, allopregnanolone solutions were administered orally (p.o.) 30 min,1 hr and 2 hr before PTZ infusion, in a volume equaling 10 ml/kg. Forthe 6-Hz seizure test, solutions of allopregnanolone in canola oil wereadministered in a volume equaling 20 ml/kg.

PTZ Seizure Threshold Test.

The threshold for various behavioral seizure stages induced by the GABAreceptor antagonist PTZ, was determined by infusing PTZ via a 27-gauge,0.75-inch “butterfly” needle inserted into the lateral tail vein. Theneedle was secured to the tail vein by a narrow piece of adhesive tape,and the animal was permitted to move freely inside an inverted plasticcontainer with free aeration from the top. PTZ (10 mg/ml) were infusedat a constant rate of 0.5 ml/min using a 1-ml syringe (BD Biosciences,Franklin Lakes, N.J.) mounted on a Harvard infusion pump (HarvardApparatus Inc., Holliston, Mass.). The syringe was connected to theneedle by polyethylene tubing. The infusion was stopped at 3 min or atthe onset of tonic extension, whichever occurred first. The thresholdsto the onset of tonic hindlimb extension were determined by measuringthe latency from the start of convulsant infusion to the onset of allthe response. The threshold value (milligrams per kilogram) wasdetermined according to the following formula: (infusion duration[seconds]×infusion rate [milliliters per minute]×convulsant drugconcentration [milligrams per milliliter]×1000)/(60 s×weight of mouse[grams]).

6-Hz Seizure Test.

Mice were tested with a 3-s corneal stimulus (200-μs duration, 32-mAmonopolar rectangular pulses at 6 Hz) delivered by a constant-currentdevice (ECT Unit 5780; Ugo Basile, Comerio, Italy). Ocular anesthetic(0.5% tetracaine) was applied to the corneas 15 min before stimulation.Immediately before stimulation, the corneal electrodes were wetted withsaline to provide good electrical contact. The seizures were oftenpreceded by a period of intense locomotor agitation (wild running andjumping). The animals then exhibited a “stunned” posture associated withrearing (bipedal standing), forelimb automatic movements and clonus,twitching of the vibrissae, and Straub-tail. The duration of the seizureactivity ranged from 60 to 120 s in untreated animals. Animals resumedtheir normal exploratory behavior after the seizure. Animals were scoredas protected or not protected. An animal was considered protected if itresumed its normal exploratory behavior within 10 s of stimulation.

Discussion

There are many potential clinical applications of the neurosteroidallopregnanolone. For some of these applications, the preferred route ofadministration is by mouth. However, absorption of orally administeredallopregnanolone is poor so that oral administration is not practical. Amethod to overcome this limitation has been discovered. Allopregnanolonewas found to readily dissolve in three oils. When dissolved in miglyol,allopregnanolone exhibited no bioactivity in the PTZ seizure thresholdtest. Surprisingly, however, when dissolved in canola oil or peanut oil,activity was obtained in the PTZ seizure threshold test.Allopregnanolone dissolved in canola oil also had activity in the 6-Hzseizure test. Allopregnanolone dissolved in canola oil or peanut oil hadno or only minimal activity 30 min after administration but had strongactivity at 60 min after administration and in some cases activity wasalso present 120 to 240 min after administration.

These results confirm that allopregnanolone has anti-seizure activity.Dissolving allopregnanolone in canola oil and peanut oil provides apractical method to deliver the neurosteroid by the oral route. Whendissolved in these oils, allopregnanolone confers long-lastinganti-seizure activity. Surprisingly, allopregnanolone was highlyactivity only when dissolved in canola oil and peanut oil; no activitywas obtained when the neurosteroid was dissolved in miglyol. Thediscovery of activity with solutions in canola oil and peanut oil isunexpected.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A composition comprising a steroid and an edible oil.
 2. Acomposition consisting essentially of a steroid and an edible oil. 3.The composition of claim 1, wherein the steroid is a neurosteroid. 4.The composition of claim 3, wherein the neurosteroid is selected fromthe group consisting of allopregnanolone,allotetrahydrodeoxycorticosterone, ganaxolone, alphaxolone, alphadolone,hydroxydione, minaxolone, and Althesin.
 5. The composition of claim 3,wherein the neurosteroid is allopregnanolone.
 6. The composition ofclaim 1, wherein the steroid is suspended or dissolved in the edibleoil.
 7. The composition of claim 1, wherein the edible oil comprises oneor more vegetable oils.
 8. The composition of claim 7, wherein thevegetable oil is selected from the group consisting of coconut oil, cornoil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil,canola oil, safflower oil, sesame oil, soybean oil, sunflower oil, andmixtures thereof.
 9. The composition of claim 1, wherein the edible oilis canola oil.
 10. The composition of claim 1, wherein the edible oil ispeanut oil.
 11. The composition of claim 1, wherein the edible oilcomprises one or more nut oils.
 12. The composition of claim 11, whereinthe nut oil is selected from the group consisting of almond oil, cashewoil, hazelnut oil, macadamia oil, mongongo nut oil, pecan oil, pine nutoil, pistachio oil, walnut oil, and mixtures thereof.
 13. Thecomposition of claim 1, wherein the composition is contained within asoft gel capsule for oral delivery to a subject.
 14. The composition ofclaim 1, wherein the steroid is not progesterone.
 15. The composition ofclaim 1, wherein the composition comprises or consists essentially ofallopregnanolone and canola oil.
 16. The composition of claim 1, whereinthe composition comprises or consists essentially of allopregnanoloneand peanut oil.
 17. A method of treating, reducing, and/or mitigatingsymptoms associated with and/or caused by traumatic brain injury,Alzheimer's disease, epilepsy, anxiety, fragile X syndrome,post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, andsmoking cessation in a subject in need thereof, comprisingadministration to the subject orally or transmucosally a composition ofclaim
 1. 18. The method of claim 17, wherein the composition isadministered orally.
 19. A method of treating, reducing, and/ormitigating symptoms associated with and/or caused by epilepsy, in asubject in need thereof, comprising administration to the subject orallyor transmucosally a composition of claim
 1. 20. A method of acceleratingthe termination or abortion of an impending seizure in a subject in needthereof, comprising administration to the subject orally ortransmucosally a composition of claim
 1. 21. The method of claim 19,wherein the subject is experiencing aura.
 22. The method of claim 19,wherein the subject has been warned of an impending seizure.
 23. Themethod of claim 19, wherein the subject is experiencing a seizure. 24.The method of claim 19, wherein the subject has status epilepticus. 25.The method of claim 19, wherein the subject has myoclonic epilepsy. 26.The method of claim 19, wherein the subject suffers from seizureclusters.
 27. The method of claim 23, wherein the seizure is a tonicseizure.
 28. The method of claim 23, wherein the seizure is a clonicseizure.